FDX1 Depletion Activates CD8+ T Cell Antitumor Immunity by Promoting DMBT1 Secretion in Cuproptosis of Colorectal Cancer.

Cuproptosis, a copper-dependent form of regulated cell death, has been documented in colorectal cancer (CRC), yet its impact on the tumor immune microenvironment remains incompletely understood. Here, we demonstrate that elesclomol-induced cuproptosis potently activates innate and adaptive antitumor immunity, markedly enhancing CD8+ T cell cytotoxicity while attenuating exhaustion. Mechanistically, FDX1, which correlates inversely with CD8+ T cell infiltration and predicts poor prognosis, functions as a core regulator of CD8+ T cell functionality during cuproptosis. FDX1 promotes CRC proliferation and metastasis while suppressing CD8+ T cell cytokine production. We further show that FDX1 binds DICER1 to reduce DMBT1 mRNA stability, with FDX1 and DMBT1 expression exhibiting significant negative correlation in CRC tissues. Our findings establish the FDX1-DICER1-DMBT1 axis as a critical regulator of CRC progression and immune evasion, suggesting that therapeutic targeting of this pathway could enhance antitumor immunity and overcome resistance to existing immunotherapies.